bims-amsmem 2022-06-12 papers

bims-amsmem

Biomed News

on AMPK signaling mechanism in energy metabolism

Issue of 2022–06–12
28 papers selected by
Dipsikha Biswas, Københavns Universitet

AMPK facilitates the hypoxic ventilatory response through non-adrenergic mechanisms at the brainstem.
Salidroside attenuates myocardial ischemia/reperfusion injury via AMPK-induced suppression of endoplasmic reticulum stress and mitochondrial fission.
AMPK and the Challenge of Treating Hypoxic Pulmonary Hypertension.
AMPK Modulates the Metabolic Adaptation of C6 Glioma Cells in Glucose-Deprived Conditions without Affecting Glutamate Transport.
Tumor protein D52 (TPD52) affects cancer cell metabolism by negatively regulating AMPK.
Low-dose metformin and PEN2-dependent lysosomal AMPK activation: benefits outnumber side effects.
Inhibition of basal and glucagon-induced hepatic glucose productionby 991 and other pharmacological AMPK activators.
Myostatin Deficiency Enhances Antioxidant Capacity of Bovine Muscle via the SMAD-AMPK-G6PD Pathway.
Dietary supplementation with metformin improves testis function and semen quality and increases antioxidants and autophagy capacity in goats.
Knockdown of miRNA-134-5p rescues dendritic deficits by promoting AMPK-mediated mitophagy in a mouse model of depression.
Polyethylene glycol capped gold nanoparticles ameliorate renal ischemia-reperfusion injury in diabetic mice through AMPK-Nrf2 signaling pathway.
Glutamine in suppression of lipopolysaccharide-induced piglet intestinal inflammation: The crosstalk between AMPK activation and mitochondrial function.
Effects of Oat Complex High-Fiber Formula Powder on the Composition of Intestinal Microbiota and Enzyme Activities in Mice Induced by a High-Fat Diet.
Impacts of altered exercise volume, intensity, and duration on the activation of AMPK and CaMKII and increases in PGC-1α mRNA.
Exosomal EPHA2 derived from highly metastatic breast cancer cells promotes angiogenesis by activating the AMPK signaling pathway through Ephrin A1-EPHA2 forward signaling.
Daming capsule protects against myocardial infarction by promoting mitophagy via the SIRT1/AMPK signaling pathway.
Haizao Yuhu decoctions including three species of glycyrrhiza protected against propylthiouracil-induced goiter with hypothyroidism in rats via the AMPK/mTOR pathway.
AMPK/mTOR-driven autophagy & Nrf2/HO-1 cascade modulation by amentoflavone ameliorates indomethacin-induced gastric ulcer.
Plant sterol ester of α-linolenic acid improved non-alcoholic fatty liver disease by attenuating endoplasmic reticulum stress-triggered apoptosis via activation of the AMPK.
Beta-Sitosterol Modulates the Migration of Vascular Smooth Muscle Cells via the PPARG/AMPK/mTOR Pathway.
Bushen Huoxue Formula Modulates Autophagic Flux and Inhibits Apoptosis to Protect Nucleus Pulposus Cells by Restoring the AMPK/SIRT1 Pathway.
Differential expression of glucose metabolism-related genes and AMP-activated protein kinases in crop tissue of male and female pigeons (Columba livia domestica) during the incubation and chick-rearing periods.
The Anti-hyperuricemia and Anti-inflammatory Effects of Atractylodes Macrocephala in Hyperuricemia and Gouty Arthritis Rat Models.
Octacosanol Modifies Obesity, Expression Profile and Inflammation Response of Hepatic Tissues in High-Fat Diet Mice.
Eucalyptol relieves imidacloprid-induced autophagy through the miR-451/Cab39/AMPK axis in Ctenopharyngodon idellus kidney cells†.
Metformin attenuates depressive-like behavior of methamphetamine withdrawal in mice: A mechanistic approach.
PGAM1 regulation of ASS1 contributes to the progression of breast cancer through the cAMP/AMPK/CEBPB pathway.
Retraction Note: Curcumin synergizes with 5-fluorouracil by impairing AMPK/ULK1-dependent autophagy, AKT activity and enhancing apoptosis in colon cancer cells with tumor growth inhibition in xenograft mice.

Pflugers Arch. 2022 Jun 10.

AMPK facilitates the hypoxic ventilatory response through non-adrenergic mechanisms at the brainstem.

Sandy MacMillan, A Mark Evans.

  We recently demonstrated that the hypoxic ventilatory response (HVR) is facilitated by the AMP-activated protein kinase (AMPK) in catecholaminergic neural networks that likely lie downstream of the carotid bodies within the caudal brainstem. Here, we further subcategorise the neurons involved, by cross-comparison of mice in which the genes encoding the AMPK-α1 (Prkaa1) and AMPK-α2 (Prkaa2) catalytic subunits were deleted in catecholaminergic (TH-Cre) or adrenergic (PNMT-Cre) neurons. As expected, the HVR was markedly attenuated in mice with AMPK-α1/α2 deletion in catecholaminergic neurons, but surprisingly was modestly augmented in mice with AMPK-α1/α2 deletion in adrenergic neurons when compared against a variety of controls (TH-Cre, PNMT-Cre, AMPK-α1/α2 floxed). Moreover, AMPK-α1/α2 deletion in catecholaminergic neurons precipitated marked hypoventilation and apnoea during poikilocapnic hypoxia, relative to controls, while mice with AMPK-α1/α2 deletion in adrenergic neurons entered relative hyperventilation with reduced apnoea frequency and duration. We conclude, therefore, that AMPK-dependent modulation of non-adrenergic networks may facilitate increases in ventilatory drive that shape the classical HVR, whereas AMPK-dependent modulation of adrenergic networks may provide some form of negative feedback or inhibitory input to moderate HVR, which could, for example, protect against hyperventilation-induced hypocapnia and respiratory alkalosis.

Keywords:  AMPK; Adrenergic; Apnoea; Catecholaminergic; Hypoxia; Hypoxic ventilatory response

DOI:  https://doi.org/10.1007/s00424-022-02713-8
Toxicol Appl Pharmacol. 2022 May 31. pii: S0041-008X(22)00238-1. [Epub ahead of print]448 116093

Salidroside attenuates myocardial ischemia/reperfusion injury via AMPK-induced suppression of endoplasmic reticulum stress and mitochondrial fission.

Xin Tian, Ye Huang, Xiaofeng Zhang, Rong Fang, Yi Feng, Wanfang Zhang, Ling Li, Tian Li.

  Ischemic heart disease (IHD) is the primary cause of death worldwide. Salidroside (Sal), the major active compound derived from Rhodiola rosea, is believed to have cardioprotective effects. AMP-activated protein kinase (AMPK), is a pivotal AMP-activated protein kinase in energy metabolism. Whether Sal plays an anti-endoplasmic reticulum stress/mitochondrial fission role through AMPK remains elusive. In this study, we established a myocardial ischemia/reperfusion (I/R) rat model. Rat hearts exposed to Sal with or without compound C were then subjected to I/R. Further, H9c2 cardiomyocytes were subjected to simulated ischemia/reperfusion (SIR) by hypoxia-reoxygenation. The rats and cardiomyocytes were pretreated with Sal, followed by Compound C and AMPK-siRNA to block AMPK activity. We found that Sal significantly ameliorated cardiac function, mitigated infarct size and serum content of lactate dehydrogenase and creatine kinase, improved mitochondrial function, and reduced mitochondrial fission and apoptosis. Furthermore, in cultured H9c2 cardiomyocytes, Sal increased the cell viability and inhibited SIR-induced myocardial apoptosis and mitochondrial fission. Furthermore, the translocation of Drp1 from the cytoplasm to mitochondria induced by salidroside was confirmed both in vivo and in vitro. However, the use of Compound C or AMPK siRNA to block AMPK activity leads to blockade of the protective effects of Sal. In summary, protects against myocardial I/R by activating the AMPK signaling pathway, inhibiting ER stress, and reducing mitochondrial fission and apoptosis.

Keywords:  AMPK; Apoptosis; Endoplasmic reticulum stress; Mitochondrial fission; Myocardial ischemia/reperfusion injury; Salidroside

DOI:  https://doi.org/10.1016/j.taap.2022.116093
Int J Mol Sci. 2022 Jun 01. pii: 6205. [Epub ahead of print]23(11):

AMPK and the Challenge of Treating Hypoxic Pulmonary Hypertension.

Karen Flores, Patricia Siques, Julio Brito, Silvia M Arribas.

  Hypoxic pulmonary hypertension (HPH) is characterized by sustained elevation of pulmonary artery pressure produced by vasoconstriction and hyperproliferative remodeling of the pulmonary artery and subsequent right ventricular hypertrophy (RVH). The search for therapeutic targets for cardiovascular pathophysiology has extended in many directions. However, studies focused on mitigating high-altitude pulmonary hypertension (HAPH) have been rare. Because AMP-activated protein kinase (AMPK) is involved in cardiovascular and metabolic pathology, AMPK is often studied as a potential therapeutic target. AMPK is best characterized as a sensor of cellular energy that can also restore cellular metabolic homeostasis. However, AMPK has been implicated in other pathways with vasculoprotective effects. Notably, cellular metabolic stress increases the intracellular ADP/ATP or AMP/ATP ratio, and AMPK activation restores ATP levels by activating energy-producing catabolic pathways and inhibiting energy-consuming anabolic pathways, such as cell growth and proliferation pathways, promoting cardiovascular protection. Thus, AMPK activation plays an important role in antiproliferative, antihypertrophic and antioxidant pathways in the pulmonary artery in HPH. However, AMPK plays contradictory roles in promoting HPH development. This review describes the main findings related to AMPK participation in HPH and its potential as a therapeutic target. It also extrapolates known AMPK functions to discuss the less-studied HAPH context.

Keywords:  AMPK; cardioprotection; high altitude; hypoxic pulmonary hypertension

DOI:  https://doi.org/10.3390/ijms23116205
Cells. 2022 May 31. pii: 1800. [Epub ahead of print]11(11):

AMPK Modulates the Metabolic Adaptation of C6 Glioma Cells in Glucose-Deprived Conditions without Affecting Glutamate Transport.

Inês Belo do Nascimento, Marie Verfaillie, Gamze Ates, Pauline Beckers, Virginie Joris, Nathalie Desmet, Ann Massie, Emmanuel Hermans.

  Energy homeostasis in the central nervous system largely depends on astrocytes, which provide metabolic support and protection to neurons. Astrocytes also ensure the clearance of extracellular glutamate through high-affinity transporters, which indirectly consume ATP. Considering the role of the AMP-activated protein kinase (AMPK) in the control of cell metabolism, we have examined its implication in the adaptation of astrocyte functions in response to a metabolic stress triggered by glucose deprivation. We genetically modified the astrocyte-like C6 cell line to silence AMPK activity by overexpressing a dominant negative mutant of its catalytic subunit. Upon glucose deprivation, we found that C6 cells maintain stable ATP levels and glutamate uptake capacity, highlighting their resilience during metabolic stress. In the same conditions, cells with silenced AMPK activity showed a reduction in motility, metabolic activity, and ATP levels, indicating that their adaptation to stress is compromised. The rate of ATP production remained, however, unchanged by AMPK silencing, suggesting that AMPK mostly influences energy consumption during stress conditions in these cells. Neither AMPK modulation nor prolonged glucose deprivation impaired glutamate uptake. Together, these results indicate that AMPK contributes to the adaptation of astrocyte metabolism triggered by metabolic stress, but not to the regulation of glutamate transport.

Keywords:  ATP; astrocyte; glucose deprivation; glutamate transporter; metabolic stress

DOI:  https://doi.org/10.3390/cells11111800
Cancer Med. 2022 Jun 06.

Tumor protein D52 (TPD52) affects cancer cell metabolism by negatively regulating AMPK.

Yali Chen, Changmin Peng, Wei Tan, Jia Yu, Jacqueline Zayas, Yihan Peng, Zhenkun Lou, Huadong Pei, Liewei Wang.

   BACKGROUND: The AMP-activated protein kinase (AMPK) is a central regulator of energy homeostasis, with deregulation leading to cancer and other diseases. However, how this pathway is dysregulated in cancer has not been well clarified.
METHODS: Using a tandem affinity purification/mass-spec technique and biochemical analyses, we identified tumor protein D52 (TPD52) as an AMPKα-interacting molecule. To explore the biological effects of TPD52 in cancers, we conducted biochemical and metabolic assays in vitro and in vivo with cancer cells and TPD52 transgenic mice. Finally, we assessed the clinical significance of TPD52 expression in breast cancer patients using bioinformatics techniques.
RESULTS: TPD52, initially identified to be overexpressed in many human cancers, was found to form a stable complex with AMPK in cancer cells. TPD52 directly interacts with AMPKα and inhibits AMPKα kinase activity in vitro and in vivo. In TPD52 transgenic mice, overexpression of TPD52 leads to AMPK inhibition and multiple metabolic defects. Clinically, high TPD52 expression predicts poor survival of breast cancer patients.
CONCLUSION: The ﬁndings revealed that TPD52 is a novel regulator of energy stress-induced AMPK activation and cell metabolism. These results shed new light on AMPK regulation and understanding of the etiology of cancers with TPD52 overexpression.

Keywords:  AMP-activated protein kinase (AMPK); cell metabolism; tumor protein D52 (TPD52)

DOI:  https://doi.org/10.1002/cam4.4911
Signal Transduct Target Ther. 2022 Jun 04. 7(1): 178

Low-dose metformin and PEN2-dependent lysosomal AMPK activation: benefits outnumber side effects.

Longlong Liu, Pradeep Kumar Patnana, Subbaiah Chary Nimmagadda.

DOI: https://doi.org/10.1038/s41392-022-01040-9
Biochem J. 2022 Jun 07. pii: BCJ20220170. [Epub ahead of print]

Inhibition of basal and glucagon-induced hepatic glucose productionby 991 and other pharmacological AMPK activators.

Manuel Johanns, Cyril Corbet, Roxane Jacobs, Melissa Drappier, Guido T Bommer, Gaëtan Herinckx, Didier Vertommen, Nicolas Tajeddine, David Young, Joris Messens, Olivier Feron, Gregory R Steinberg, Louis Hue, Mark H Rider.

  Pharmacological AMPK activation represents an attractive approach for the treatment of type 2 diabetes (T2D). AMPK activation increases skeletal muscle glucose uptake, but there is controversy as to whether AMPK activation also inhibits hepatic glucose production (HGP) and pharmacological AMPK activators can have off-target effects that contribute to their anti-diabetic properties. The main aim was to investigate the effects of 991 and other direct AMPK activators on HGP and determine whether observed effects were AMPK-dependent. In incubated hepatocytes, 991 substantially decreased gluconeogenesis from lactate, pyruvate and glycerol, but not from other substrates. Hepatocytes from AMPKβ1-/- mice had substantially reduced liver AMPK activity, yet the inhibition of glucose production by 991 persisted. Also, the glucose-lowering effect of 991 was still seen in AMPKβ1-/- mice subjected to an intraperitoneal pyruvate tolerance test. The AMPK-independent mechanism by which 991 treatment decreased gluconeogenesis could be explained by inhibition of mitochondrial pyruvate uptake and inhibition of mitochondrial sn-glycerol-3-phosphate dehydrogenase-2. However, 991 and new-generation direct small-molecule AMPK activators antagonized glucagon-induced gluconeogenesis in an AMPK-dependent manner. Our studies support the notion that direct pharmacological activation of hepatic AMPK as well as inhibition of pyruvate uptake could be an option for the treatment of T2D-linked hyperglycaemia.

Keywords:  Direct AMPK activators; Gluconeogenesis; Glycerol phosphate dehydrogenase; Pyruvate tolerance test; Pyruvate transport

DOI:  https://doi.org/10.1042/BCJ20220170
Oxid Med Cell Longev. 2022 ;2022 3497644

Myostatin Deficiency Enhances Antioxidant Capacity of Bovine Muscle via the SMAD-AMPK-G6PD Pathway.

Lin Zhu, Xueqiao Wang, Zhuying Wei, Miaomiao Yang, Xinyu Zhou, Jiaru Lei, Chunling Bai, Guanghua Su, Xuefei Liu, Lei Yang, Guangpeng Li.

During exercise, the body's organs and skeletal muscles produce reactive oxygen species (ROS). Excessive ROS can destroy cellular lipids, sugars, proteins, and nucleotides and lead to cancer. The production of nicotinamide adenine dinucleotide phosphate (NADPH) by the pentose phosphate pathway (PPP) is an auxiliary process of the cellular antioxidant system that supplements the reducing power of glutathione (GSH) to eliminate ROS in the cell. Myostatin (MSTN) is mainly expressed in skeletal muscle and participates in the regulation of skeletal muscle growth and development. Loss of MSTN leads to muscular hypertrophy, and MSTN deficiency upregulates glycolysis. However, the effect of MSTN on the PPP has not been reported. This study investigated the effect of MSTN on muscle antioxidant capacity from a metabolic perspective. We found that reducing MSTN modulates AMP-activated protein kinase (AMPK), a key molecule in cellular energy metabolism that directly regulates glucose metabolism through phosphorylation. Downregulation of MSTN promotes tyrosine modification of glucose-6-phosphate-dehydrogenase (G6PD) by AMPK and is regulated by the Smad signaling pathway. The Smad2/3 complex acts as a transcription factor to inhibit the AMPK expression. These results suggest that reduced MSTN expression inhibits the Smad signaling pathway, promotes AMPK expression, enhances the activity of G6PD enzyme, and enhances the antioxidant capacity of nonenzymatic GSH.

DOI: https://doi.org/10.1155/2022/3497644
Theriogenology. 2022 Jun 02. pii: S0093-691X(22)00211-4. [Epub ahead of print]188 79-89

Dietary supplementation with metformin improves testis function and semen quality and increases antioxidants and autophagy capacity in goats.

Jie Zhao, Peng-Cheng Yang, Hua Yang, Zhi-Bo Wang, M A El-Samahy, Feng Wang, Yan-Li Zhang.

  ATP is essential for mammalian sperm to maintain fertilizing capacity. Metformin (Met) can activate 5'-AMP-activated protein kinase (AMPK) to maintain energy homeostasis. Thus, the aim of the present study was to investigate whether Met can improve testis function, semen quality, antioxidant and autophagy capacity through AMPK mediation of energy metabolism in goats. Twelve adult goats were randomly divided into three dietary treatments. All goats were fed a basal diet for 3 weeks and then assigned to a Met supplementation diet containing 0, 150, or 300 mg/kg for 8 weeks. The results showed that sperm viability, sperm membranal functional integrity, and acrosome integrity increased (P < 0.05) relative to the other treatments in the 300 mg/kg Met group. Growth hormone (GH) and insulin-like growth factor (IGF-1) in the 300 mg/kg Met group significantly decreased (P < 0.05) relative to the control group. Estrogen levels (E2) in the 300 mg/kg Met group remarkably improved (P < 0.05) compared with the control group. The activities of the antioxidant enzymes catalase (CAT), glutathione peroxidase (GSH-px), and superoxide dismutase (SOD) significantly increased (P < 0.05) in the 300 mg/kg Met group relative to the control group. A significant increase in AMPK and p-AMPK protein expression in the 300 mg/kg Met group was observed relative to the control group (P < 0.05). Belicin-1 and LC3II/I protein expression was significantly increased by adding Met to the diet (P < 0.05) and reached a maximum in the 300 mg/kg Met group. In addition, differentially expressed genes (DEGs) of goat testis were confirmed by RNA-seq. GO enrichment analysis revealed that DEGs were enriched in testicular metabolism and sperm development-related functional pathways. Overall, the results indicate that Met may play an important role in the regulation of testis function, semen quality, antioxidant, and autophagy capacity. These findings will help elucidate the role of Met in goat testis development.

Keywords:  Apoptosis; Autophagy; Go analysis; Male reproductive function; Metabolism

DOI:  https://doi.org/10.1016/j.theriogenology.2022.05.030
Neuropharmacology. 2022 Jun 01. pii: S0028-3908(22)00213-1. [Epub ahead of print]214 109154

Knockdown of miRNA-134-5p rescues dendritic deficits by promoting AMPK-mediated mitophagy in a mouse model of depression.

Guoli Wang, Ying Liu, Xuejie Zhu, Kehao Lin, Mingkai Li, Zhenke Wu, Ronghua Zhang, Qiusheng Zheng, Defang Li, Tianyue An.

  Neuronal dendrites and dendritic spines are essential for normal synaptic transmission and may be critically involved in the pathophysiology of various neurological disorders, including depression. Emerging data supports the role of mitochondria in dendritic protrusions in modulating the development and morphological plasticity of spines. Mitophagy, a mitochondria-specific form of autophagy, is the fundamental process of clearing damaged mitochondria to maintain cellular homeostasis. As a brain-specific microRNA, miR-134 is localized to the synaptodendritic compartment of hippocampal neurons and negatively regulates the development of dendritic spines. However, the role of miR-134 in mitophagy related to dendritic deficits in the pathophysiology of depression remains unclear. In this study, we showed that miR-134-5p knockdown abrogated depression-like behavioral symptoms and corrected aberrant spine morphology in hippocampal neurons of chronic unpredictable mild stress (CUMS) mice. Moreover, knockdown of miR-134-5p triggered autophagy in dendrites, improved mitochondrial impairment, and induced the generation of autophagosomes in the hippocampus of CUMS mice. We further found that AMP-activated protein kinase (AMPK), which mediates the impairment of defective mitochondria via mitophagy, can bind directly to miR-134-5p and is negatively regulated by this miRNA. This study demonstrates that miR-134-5p exerts an enormous effect on dendritic deficits by promoting AMPK-mediated mitophagy and provides a potential new target for antidepressant drug research and development.

Keywords:  AMPK signaling Pathway; Dendrite; Depression; Mitophagy; miR-134-5p

DOI:  https://doi.org/10.1016/j.neuropharm.2022.109154
Environ Sci Pollut Res Int. 2022 Jun 10.

Polyethylene glycol capped gold nanoparticles ameliorate renal ischemia-reperfusion injury in diabetic mice through AMPK-Nrf2 signaling pathway.

Hanan Saleh, Mohamed Salama, Rehab Mohamed Hussein.

  The aim of this study is to investigate the protective effect of polyethylene glycol capped gold nanoparticles (PEG-AuNPs) on renal ischemia-reperfusion injury (I/R)-induced acute kidney injury (AKI) in diabetic mice via the activation of adenosine 5' monophosphate-activated protein kinase-nuclear factor erythroid-2-related factor-2 (AMPK-Nrf2) pathway. Diabetes was induced in male mice (12/group) by streptozotocin (50 mg/kg) for 5 consecutive days. After 4 weeks, the mice have intravenously received doses of PEG-AuNPs (40, 150, and 400 µg/kg body weight) for 3 consecutive days, and then animals were subjected to 30 min ischemia and 48 h reperfusion. Following the treatment with three different doses of PEG-AuNPs, the levels of blood urea nitrogen (BUN) and creatinine were reduced. Obvious reduction in renal tubular atrophy, glomerular damage, mitochondrial damage, and necrotic area were ultra-structurally detected, and renal interstitial inflammation and apoptosis were diminished. Moreover, PEG-AuNPs increased the recovering of damaged renal cells, suppressed significantly levels of malondialdehyde (MDA), downregulated significantly the level of inflammatory cytokines (TNF-α and IL-1β), and upregulated the AMPK-Nrf2 pathway. PEG-AuNPs exhibited a promising alternative therapeutic target for diabetic renal I/R-induced AKI through upregulation of AMPK/PI3K/AKT path which additionally stimulated Nrf2-regulated antioxidant enzymes in a dose-dependent manner.

Keywords:  AMPK; Diabetes; Nrf2; Oxidative stress; PEG-AuNPs; Renal ischemia/reperfusion

DOI:  https://doi.org/10.1007/s11356-022-21235-5
Anim Nutr. 2022 Sep;10 137-147

Glutamine in suppression of lipopolysaccharide-induced piglet intestinal inflammation: The crosstalk between AMPK activation and mitochondrial function.

Liuqin He, Xihong Zhou, Ziping Wu, Yanzhong Feng, Di Liu, Tiejun Li, Yulong Yin.

  The study was conducted to investigate the regulatory mechanism of glutamine (Gln) on intestinal inflammation in an Escherichia coli lipopolysaccharide (E. coli LPS)-induced in vivo and in vitro models. Piglets (n = 8) weaned at 21 d of age were fed a basal diet (control and LPS groups) or 1% Gln diet (Gln + LPS group) ad libitum for 4 weeks. On d 22, 24, 26 and 28, piglets in the LPS and Gln + LPS groups were intraperitoneally injected with E. coli LPS. Intestinal porcine epithelial cells (IPEC-J2) (n = 6) induced by LPS were used to assess related mechanisms and compound C was used to inhibit adenosine 5'-monophosphate-activated protein kinase (AMPK) activity. Our current results showed that compared with the LPS treatment, the Gln + LPS treatment had better growth performance and greater villus height (P < 0.05), and the Gln + LPS treatment reduced the rate of diarrhea by 6.4% (P < 0.05); the Gln + LPS treatment decreased serum tumor necrosis factor (TNF-ɑ), interleukin-6 (IL-6), K+, cortisol and insulin levels, whereas increased (P < 0.05) serum immunoglobulin M and epidermal growth factor levels; the Gln + LPS treatment increased (P < 0.05) the expression of aquaporins and AMPK pathway-associated targets in the jejunum and ileum of piglets, whereas decreased the expression of ion transporters (P < 0.05). The in vitro results showed that 4 mmol/L Gln administration could inhibit (P < 0.05) cell apoptosis and interleukin-1β (IL-1β), IL-6 and TNF-ɑ secretion in LPS-induced IPEC-J2 cells, promote (P < 0.05) mitochondrial respiratory metabolism and increase (P < 0.05) the number of mitochondria and mitochondrial membrane potential. The activity of AMPK was elevated by 70% to 300% in Gln-treated IPEC-J2 cells under LPS challenge or normal conditions. Our results indicate that pre-administration of Gln to piglets suppresses intestinal inflammation by modulating the crosstalk between AMPK activation and mitochondrial function.

Keywords:  AMPK; Glutamine; Intestinal inflammation; Mitochondrial function; Weaned piglet

DOI:  https://doi.org/10.1016/j.aninu.2022.03.001
Front Nutr. 2022 ;9 871556

Effects of Oat Complex High-Fiber Formula Powder on the Composition of Intestinal Microbiota and Enzyme Activities in Mice Induced by a High-Fat Diet.

Rui Huo, Meili Zhang, Yakun Zhang, Xue Bai, Yuanyuan Zhang, Xinyue Guo.

  Using oat-corn-konjac extruded mixed powder, oat bran micro powder, skim milk powder, Pueraria whole powder, and pumpkin powder as raw materials, a formula powder with high dietary fiber was prepared, and its effect on obesity in mice with a high-fat diet was investigated. After 7 days of adaptive feeding, the mice were divided into blank group, high-fat diet group, formula powder + high-fat diet group, and weight-loss drug + high-fat diet group. After 8 weeks of treatment, the body weight of mice were observed and measured to determine the composition of tract flora, liver leptin content, insulin content, and activities of AMP-activated protein kinase (AMPK), lipoprotein lipase (LPL), fatty acid synthetase (FAS), sterol-regulatory element-binding proteins (SREBPs), and acetyl CoA carboxylase 1 (ACC1). The results indicated that treatment with the formula powder could reduce the body weight of mice and increase the abundance of Bifidobacterium, Akkermansia, and Romboutsia compared to the group given a high-fat diet. Moreover, the leptin and insulin contents of the experimental group decreased from 5.67 μg/L to 0.12 μg/L and from 12.71 μg/L to 7.13 μg/L, respectively, compared to the control group, which was not significantly different from the blank group (P > 0.05). Also, the activities of AMPK and LPL increased, and the activities of FAS, SREBPs, and ACC1 were significantly decreased (P < 0.05). Some pathogenic bacteria were significantly positively correlated with leptin and FAS and significantly negatively correlated with LPL. Some beneficial bacteria were positively correlated with LPL. Therefore, the formula powder used in this study could reduce the body weight of mice, increase the abundance of some beneficial bacteria in the colonic intestinal microbiota, and improve the activities of enzymes related to lipid metabolism in the liver. This study provides a theoretical reference for the pathway by which high-fiber diet improves liver and intestinal metabolic abnormalities.

Keywords:  AMPK; dietary fiber; formula powder; intestinal flora; lipid metabolism; oat

DOI:  https://doi.org/10.3389/fnut.2022.871556
Semin Cell Dev Biol. 2022 Jun 06. pii: S1084-9521(22)00173-2. [Epub ahead of print]

Impacts of altered exercise volume, intensity, and duration on the activation of AMPK and CaMKII and increases in PGC-1α mRNA.

Brendon J Gurd, Eveline Soares Menezes, Benjamin B Arhen, Hashim Islam.

  The purpose of this review is to explore and discuss the impacts of augmented training volume, intensity, and duration on the phosphorylation/activation of key signaling protein - AMPK, CaMKII and PGC-1α - involved in the initiation of mitochondrial biogenesis. Specifically, we explore the impacts of augmented exercise protocols on AMP/ADP and Ca2+ signaling and changes in post exercise PGC - 1α gene expression. Although AMP/ADP concentrations appear to increase with increasing intensity and during extended durations of higher intensity exercise AMPK activation results are varied with some results supporting and intensity/duration effect and others not. Similarly, CaMKII activation and signaling results following exercise of different intensities and durations are inconsistent. The PGC-1α literature is equally inconsistent with only some studies demonstrating an effect of intensity on post exercise mRNA expression. We present a novel meta-analysis that suggests that the inconsistency in the PGC-1α literature may be due to sample size and statistical power limitations owing to the effect of intensity on PGC-1α expression being small. There is little data available regarding the impact of exercise duration on PGC-1α expression. We highlight the need for future well designed, adequately statistically powered, studies to clarify our understanding of the effects of volume, intensity, and duration on the induction of mitochondrial biogenesis by exercise.

Keywords:  AMPK; CaMK; Duration; Exercise; Intensity; Mitochondrial biogenesis; PGC-1a; Volume

DOI:  https://doi.org/10.1016/j.semcdb.2022.05.016
Theranostics. 2022 ;12(9): 4127-4146

Exosomal EPHA2 derived from highly metastatic breast cancer cells promotes angiogenesis by activating the AMPK signaling pathway through Ephrin A1-EPHA2 forward signaling.

Baoai Han, He Zhang, Ruinan Tian, Hui Liu, Zhaosong Wang, Zhiyong Wang, Jianfei Tian, Yanfen Cui, Sixin Ren, Xiaoyan Zuo, Ran Tian, Ruifang Niu, Fei Zhang.

  Rationale: Angiogenesis is a fundamental process of tumorigenesis, growth, invasion and metastatic spread. Extracellular vesicles, especially exosomes, released by primary tumors promote angiogenesis and cancer progression. However, the mechanism underlying the pro-angiogenic potency of cancer cell-derived exosomes remains poorly understood. Methods: Exosomes were isolated from breast cancer cells with high metastatic potential (HM) and low metastatic potential (LM). The pro-angiogenic effects of these exosomes were evaluated by in vitro tube formation assays, wound healing assays, rat arterial ring budding assays and in vivo Matrigel plug assays. Subsequently, RNA sequencing, shRNA-mediated gene knockdown, overexpression of different EPHA2 mutants, and small-molecule inhibitors were used to analyze the angiogenesis-promoting effect of exosomal EPHA2 and its potential downstream mechanism. Finally, xenograft tumor models were established using tumor cells expressing different levels of EPHA2 to mimic the secretion of exosomes by tumor cells in vivo, and the metastasis of cancer cells were monitored using the IVIS Spectrum imaging system and Computed Tomography. Results: Herein, we demonstrated that exosomes produced by HM breast cancer cells can promote angiogenesis and metastasis. EPHA2 was rich in HM-derived exosomes and conferred the pro-angiogenic effect. Exosomal EPHA2 can be transferred from HM breast cancer cells to endothelial cells. Moreover, it can stimulate the migration and tube-forming abilities of endothelial cells in vitro and promote angiogenesis and tumor metastasis in vivo. Mechanistically, exosomal EPHA2 activates the AMPK signaling via the ligand Ephrin A1-dependent canonical forward signaling pathway. Moreover, inhibition of the AMPK signaling impairs exosomal EPHA2-mediated pro-angiogenic effects. Conclusion: Our findings identify a novel mechanism of exosomal EPHA2-mediated intercellular communication from breast cancer cells to endothelial cells in the tumor microenvironment to provoke angiogenesis and metastasis. Targeting the exosomal EPHA2-AMPK signaling may serve as a potential strategy for breast cancer therapy.

Keywords:  EPHA2; angiogenesis; breast cancer; exosomes; high metastatic potential cells

DOI:  https://doi.org/10.7150/thno.72404
Biomed Pharmacother. 2022 Jul;pii: S0753-3322(22)00551-0. [Epub ahead of print]151 113162

Daming capsule protects against myocardial infarction by promoting mitophagy via the SIRT1/AMPK signaling pathway.

Xi Sun, Yanna Han, Chaorun Dong, Huan Qu, Yahan Yu, Jiaming Ju, Yunlong Bai, Baofeng Yang.

  Myocardial infarction (MI) is a myocardial injury caused by coronary thrombosis or persistent ischemia and hypoxia. Due to its high morbidity and mortality, a safer and more effective treatment strategy is urgently needed. Daming capsule (DMC), a hypolipidemic drug, reportedly exerts cardioprotective effects in clinical and basic research, although its protective mechanism remains unknown. To investigate the mechanism underlying DMC-mediated improvement of cardiac function post-MI, C57/BL6 mice subjected to coronary artery ligation were administered DMC for 4 weeks. Our data demonstrated that DMC significantly improved cardiac structure and function compared to the saline group. Moreover, DMC inhibited inflammatory response and oxidative stress and improved mitochondrial structure and function in MI mice and hypoxia-stressed cardiomyocytes. Next, our research proved that DMC increased the expression of mitophagy receptor NLRX1. Interestingly, with the administration of DMC and siNLRX1, NLRX1 expression, mitochondria and lysosome colocalization, and mitochondrial membrane potential decreased, while mitochondrial ROS accumulation increased, suggesting that DMC promoted mitophagy to improve mitochondrial function via NLRX1 regulation. Further analysis showed that DMC activated the SIRT1/AMPK signaling pathway in vivo and in vitro. Our data showed that SIRT1 knockdown downregulated NLRX1 expression, leading to structural damage and functional impairment in mitochondria, as well as increased oxidative stress, inflammatory response, and decreased cardiac function in MI mice. Collectively, our findings reveal that DMC improves cardiac function post-MI by increasing mitophagy and inhibiting oxidative stress and inflammotory response in cardiomyocytes through the SIRT1/AMPK signaling pathway.

Keywords:  AMPK; DMC; Mitophagy; Myocardial infarction; SIRT1

DOI:  https://doi.org/10.1016/j.biopha.2022.113162
J Ethnopharmacol. 2022 Jun 06. pii: S0378-8741(22)00482-2. [Epub ahead of print] 115443

Haizao Yuhu decoctions including three species of glycyrrhiza protected against propylthiouracil-induced goiter with hypothyroidism in rats via the AMPK/mTOR pathway.

Na Li, Muyun Li, Linlin Xiu, Wenyong Liao, Yuna Ren, Haiyan Liu, Shaohong Chen, Feng Chen, Xue Yu, Angran Fan, Min Huo, Jia He, Gansheng Zhong.

   ETHNOPHARMACOLOGICAL RELEVANCE: Glycyrrhiza and sargassum are among the 18 incompatible medicaments according to traditional Chinese medicine (TCM) theory. Although it contains glycyrrhiza and sargassum, Haizao Yuhu decoction (HYD) is a classic prescription widely used as TCM to treat goiter. According to the Chinese Pharmacopoeia, glycyrrhiza is divided into three varieties: Glycyrrhiza uralensis Fish., Glycyrrhiza glabra L., and Glycyrrhiza inflata Bat. Whether the three varieties of glycyrrhiza have different efficacy or toxicity when applied in the HYD is unknown.
AIM OF THE STUDY: To explore whether the HYDs comprising three varieties of glycyrrhiza have different efficacy or toxicity when used to treat goiter in rats and the underlying mechanisms of these HYDs.
MATERIALS AND METHODS: For two weeks, the goiter model was replicated by intragastric propylthiouracil (PTU) administration. Samples were divided into the control group, model group, euthyrox group, HYD with glycyrrhiza uralensis (HYD-U) group, HYD with glycyrrhiza glabra (HYD-G) group, and HYD with glycyrrhiza inflata (HYD-I) group. After four weeks of treatment, body weight, rectal temperature, thyroid/liver/kidney coefficient, thyroid/liver/kidney function, thyroid/liver/kidney histomorphology, and thyroid ultrastructure were evaluated. Then, real-time quantitative reverse-transcription polymerase chain reaction (RTqPCR), Western blot, and immunofluorescence analyses were performed to detect genes and proteins affecting autophagy and apoptosis in thyroid cells in the AMP-activated Protein Kinases (AMPK)/Mammalian target of rapamycin (mTOR) pathway.
RESULTS: All three HYDs increased thyroid hormones (THs) levels, relieved thyroid pathological tissue and ultrastructure, and activated vital proteins and genes in the AMPK/mTOR pathway. Comparisons among the efficacy of the three HYDs indicated that HYD-U restored the THs most effectively; however, no difference in the anti-goiter effect was observed. Moreover, the three HYDs resulted in no toxicity and promoted the recovery of impaired liver and kidney function caused by PTU. Comparisons among the recovery effects of the three HYDs on the liver and kidney were the same.
CONCLUSION: Our experiments demonstrated that the three HYDs had outstanding anti-goiter effects and protected liver and kidney function. Their anti-goiter effects were attributed to AMPK/mTOR pathway-induced autophagy and apoptosis. HYD-U resulted in the best THs recovery. It was further indicated that in our present study, glycyrrhiza and sargassum were compatible in the three HYDs, thereby suggesting their safety of compounding in HYD and providing a basis for the research of the 18 incompatible medicaments.

Keywords:  AMPK/mTOR pathway; Goiter; Haizao Yuhu decoction; Protective effects; Safety of compounding; Three species of glycyrrhiza

DOI:  https://doi.org/10.1016/j.jep.2022.115443
Biomed Pharmacother. 2022 Jul;pii: S0753-3322(22)00589-3. [Epub ahead of print]151 113200

AMPK/mTOR-driven autophagy & Nrf2/HO-1 cascade modulation by amentoflavone ameliorates indomethacin-induced gastric ulcer.

Mohamed F Balaha, Ziyad S Almalki, Abdullah K Alahmari, Nehad J Ahmed, Marwa F Balaha.

  Gastric ulcer (GU) is a worldwide gastrointestinal disorder associated with NSAID use. Recently, amentoflavone proved to be a potent autophagy modulator, antioxidant, anti-inflammatory, and anti-apoptotic agent. Eight-week-old male Wistar rats received amentoflavone orally for 14 days at 25, 50, or 100 mg/kg/day. On day 14 of treatment, GU was induced by a single oral instillation of 100 mg/kg indomethacin, one hour after the last treatment. Amentoflavone dose-dependently alleviated indomethacin-induced GU, as demonstrated by repression of gastric mucosa pathological manifestations (ulcer index, ulcer surface area, histopathological deviations, and score) and increased ulcer inhibition percentage. These protective effects were due to the enhancement of gastric mucosa autophagy, as demonstrated by increased levels of beclin-1, MAP1LC3B, and CTSD, and reduced expression of p62 (SQSTM1). In addition, amentoflavone modulated the AMPK/mTOR pathway by increasing p-AMPK and reducing mTORC1 levels. Moreover, it hindered the redox aberrations by reducing MDA level and enhancing SOD activity, GSH level, and Nrf2/HO-1 cascade. Furthermore, a decrease in caspase-3 levels, Bax/Bcl-2 ratio and an increase in Bcl-2 expression suggest inhibition of the apoptotic process. Additionally, amentoflavone suppressed gastric mucosal inflammation by decreasing IL-1β, TNF-α, IFN-γ levels, IL-4, IL-6 mRNA expressions and MPO activity, and increasing IL-10 mRNA expresion. Therefore, amentoflavone could consider a promising natural agent protecting against indomethacin-induced GU.

Keywords:  AMPK/mTOR pathway; Amentoflavone; Apoptosis; Autophagy; Gastric ulcer; Oxidative stress

DOI:  https://doi.org/10.1016/j.biopha.2022.113200
J Nutr Biochem. 2022 Jun 02. pii: S0955-2863(22)00143-7. [Epub ahead of print] 109072

Plant sterol ester of α-linolenic acid improved non-alcoholic fatty liver disease by attenuating endoplasmic reticulum stress-triggered apoptosis via activation of the AMPK.

Hao Han, Tingli Xue, Jie Li, Yan Guo, Xiaoyu Li, Linqi Wang, Liyuan Pei, Mingming Zheng.

  Apoptosis is a feature of progressions steatosis to nonalcoholic steatohepatitis (NASH) and can be explained by endoplasmic reticulum stress (ERS). The present study aimed to investigate the protective effects of plant sterol ester of α-linolenic acid (PS-ALA) on ERS-triggered apoptosis in high fat diet-fed mice and oleic acid-induced hepatocytes, and further explore the underlying mechanisms. Our results showed that PS-ALA improved NAFLD in both in vivo and in vitro models. Moreover, PS-ALA treatment can attenuate ERS and associated apoptosis via inhibiting IRE1α/TRAF2/JNK signal pathway. Furthermore, we found that the protective effect of PS-ALA on ERS-triggered apoptosis was mediated by activation of AMPK as pretreatment with Compound C, an AMPK inhibitor, abolished the anti-apoptotic effect of PS-ALA. Taken together, our results illustrate that PS-ALA attenuating ERS-mediated apoptosis via activating AMPK, which provided new insights into the protective effect of PS-ALA in NAFLD.

Keywords:  AMPK; apoptosis; endoplasmic reticulum stress; nonalcoholic fatty liver disease; plant sterol ester of α-linolenic acid

DOI:  https://doi.org/10.1016/j.jnutbio.2022.109072
Pharmacology. 2022 Jun 09. 1-15

Beta-Sitosterol Modulates the Migration of Vascular Smooth Muscle Cells via the PPARG/AMPK/mTOR Pathway.

Shumiao He, Siqing He, Yuankun Chen, Xiaobao Jin, Wenjie Mei, Qun Lu.

   INTRODUCTION: The increased migration of vascular smooth muscle cells (VSMCs) is an essential pathological factor in the early development of atherosclerosis. Beta-sitosterol (BS), a natural phytosterol abundant in plant seeds, exhibits various bioactivities, including cardioprotective effects. However, its effects on VSMC migration and underlying mechanisms remain to be explored.
METHOD AND RESULT: BS inhibited the proliferation and migration of angiotensin II-induced A7r5 cells and reduced intracellular oxidative stress. Targets related to VSMC migration and the targets of BS were screened, cross-referenced, and analyzed by network pharmacology combined with molecular docking technology. The identified targets were verified at the protein and gene levels using Western blotting and quantitative PCR, respectively. BS was observed to activate peroxisome proliferator-activated receptor-γ (PPARG) and adenosine 5'-monophosphate-activated protein kinase (AMPK) and negatively regulate mammalian target of rapamycin (mTOR) expression. Furthermore, a PPARG inhibitor reversed the BS-induced activation of AMPK and mTOR.
CONCLUSION: This study indicated that regulation of the PPARG/AMPK/mTOR signaling pathway could potentially contribute to the inhibitory effects of BS on angiotensin II-induced VSMC migration.

Keywords:  Beta-sitosterol; Migration; Network pharmacology analysis; Peroxisome proliferator-activated receptor/adenosine 5’-monophosphate-activated protein kinase/mammalian target of rapamycin signaling pathway; Vascular smooth muscle cells

DOI:  https://doi.org/10.1159/000525218
Biomed Res Int. 2022 ;2022 8929448

Bushen Huoxue Formula Modulates Autophagic Flux and Inhibits Apoptosis to Protect Nucleus Pulposus Cells by Restoring the AMPK/SIRT1 Pathway.

Shang Gao, Nianhu Li, Renchang Chen, Youxiang Su, Yun Song, Songlin Liang.

Background: Low back pain (LBP) has the characteristics of chronic and persistence, which is a heavy social burden. Intervertebral disc degeneration (IVDD) is a major cause of LBP. The typical features of IVDD are extracellular matrix (ECM) degradation and nucleus pulposus cell (NP) apoptosis. Bushen Huoxue Formula (BSHXF) has good clinical effects on LBP. However, the mechanism of BSHXF affecting ECM and NP cells is still unclear. Aim of the Study. In this study, the impact of BSHXF on autophagy and apoptosis of NP cells was studied through the AMPK/SIRT1 pathway. Material and Methods. NP cells were extracted through the digestion of collagenase and trypsin, and the components of BSHXF were identified. Cell Counting Kit-8 was applied to detect the impact of BSHXF on NP cells. Mitochondrial function was detected using MitoTracker assay, ATP kit, and SOD kit. Autophagy and apoptosis were detected by RT-qPCR, western blotting, and flow cytometry.
Results: BSHXF promoted NP cell survival in a concentration-dependent manner, and the elimination of rat serum did not increase cell proliferation; TNF-α accelerated ECM degradation, ROS accumulation, and NP cell apoptosis and decreased autophagic flux. BSHXF restored mitochondrial function and autophagic flux. In addition, AMPK/SIRT1 pathway activation was associated with IVDD.
Conclusions: BSHXF regulates autophagy and enhances autophagic flux to suppress excessive ROS production and restore mitochondrial function in an AMPK/SIRT1-dependent manner. However, the protection of BSHXF on TNF-α-treated cells was eliminated by 3-MA. Furthermore, the protective impact of BSHXF on ECM degradation and apoptosis induced by TNF-α was restrained by an AMPK inhibitor. Therefore, maintaining the proper autophagy illustrates treatment strategy for IVDD.

DOI: https://doi.org/10.1155/2022/8929448
J Anim Physiol Anim Nutr (Berl). 2022 Jun 06.

Differential expression of glucose metabolism-related genes and AMP-activated protein kinases in crop tissue of male and female pigeons (Columba livia domestica) during the incubation and chick-rearing periods.

Jian-Guo Zhu, Peng Xie, Chao Song, Ting-Wu Liu, Dao-Qing Gong.

  The objective of this study was to explore the carbohydrate contents of crop milk, insulin and glucose concentrations in serum and the expression patterns of AMP-activated protein kinases (AMPKs) and genes related to glucose metabolism in pigeon crops during the breeding period. Crop milk was collected from squabs of rearing Day 1 (R1) to R6. Contents of total sugar and reducing sugar increased to the maximum levels at R6 (p < 0.05). Forty-two pairs of adult pigeons were allotted to seven groups by different breeding stages, and their crops and serum were sampled. No significant differences were found in either insulin or glucose levels in serum. The glucose transporter 2 gene level was the greatest at R15 in females, whereas it was at R7 in males. However, sodium-dependent glucose transporters 1 expression in both sexes decreased from incubation Day 17 (I17) to R7. In females, glucokinase expression peaked at R1, and at R1 and R7 in males. Pyruvate kinase mRNA levels peaked at R7 in females and at R15 males. The mRNA abundance of fructose-1,6-bisphosphatase 1 in both sexes and glucose-6-phosphatase in females decreased after I10. While phosphoenolpyruvate carboxykinase 1 expression decreased after I17 (p < 0.05). Protein levels of AMPKα in crops were minimized at R1 (p < 0.05). In females, expression of AMPKα1 and AMPKα2 was inhibited at I17 and R1 (p < 0.05). In males, AMPKα1 expression was decreased at R7 (p < 0.05) and AMPKα2 was reduced at I10 and R1. pAMPK expression was the lowest at I17 in females, and it was at R7 and R25 in males. Conclusively, glycolysis in pigeon crops was enhanced during chick-rearing, while gluconeogenesis was significantly inhibited. The stability of the insulin level suggests that it was probably not involved in the regulation of glucose metabolism in crop tissues.

Keywords:  AMP-activated protein kinases; crop milk; gluconeogenesis; glycolysis; insulin

DOI:  https://doi.org/10.1111/jpn.13741
Comb Chem High Throughput Screen. 2022 Jun 03.

The Anti-hyperuricemia and Anti-inflammatory Effects of Atractylodes Macrocephala in Hyperuricemia and Gouty Arthritis Rat Models.

Xvwu Qian, Ying Jiang, Yiyuan Luo, Yuchen Jiang.

   AIMS: Atractylodes macrocephala is a traditional Chinese medicine with a variety of pharmacological activities. This study was aimed to evaluate its anti-hyperuricemia and anti-inflammatory effects in gout, and to preliminarily explore its mechanism.
METHODS: The hyperuricemia rat model was established by intraperitoneal injection of oteracil potassium and intragastric gavage of yeast powder solution. And the acute gouty arthritis (GA) model was established by injecting monosodium urate (MSU) suspension. In the study of anti-hyperuricemia effect of Atractylodes macrocephala, the healthy male Sprague-Dawley rats were randomly divided into blank group, hyperuricemia group allopurinol group as well as low, moderate and high dose groups of Atractylodes macrocephala decoction (N=8 rats in each group). Serum, liver and kidney tissue samples were collected from each group. Serum uric acid (UA), adenosine deaminase (ADA) and xanthine oxidase (XOD) levels in each group were detected by enzyme linked immunosorbent assay (ELISA). Protein levels of ADA and XOD in liver tissues were detected by Western blot, and renal histological changes were observed by Hematoxylin-eosin (H＆E) and Masson staining. In order to investigate the anti-inflammatory effect of Atractylodes macrocephala, the healthy male Sprague-Dawley rats were randomly divided into blank group, GA group, colchicine group, high, moderate and low dose groups of Atractylodes macrocephala decoction (N=8 rats in each group), and serum and synovial tissue of each group were collected. Then the level of serum interleukin (IL)-1β and tumor necrosis factor (TNF)-α was observed by ELISA, and the histological changes of synovial tissue were observed by H＆E staining. Besides, the expression of adenosine monophosphate activated protein kinase (AMPK) /silent information regulator (SIRT) 1/ nuclear factor kappa B (NF-κB) protein in synovial tissue was observed by Western blot and immunohistochemistry. The markers of M1 and M2 macrophages, inducible nitric oxide synthase (iNOS) and arginase-1 (ARG1) were observed by Western blot and immunofluorescence.
RESULTS: Atractylodes macrocephala could reduce the production of UA by inhibiting the level of ADA and XOD, and could improve renal injury and fibrosis. In addition, Atractylodes macrophages could reduce the levels of IL-1β and TNF-α, activate AMPK/SIRT1 signaling pathway, and inhibit the activation of NF-κB and the polarization of macrophages to a pro-inflammatory phenotype.
CONCLUSION: Atractylodes macrocephala shows good anti-hyperuricemic and anti-inflammatory effects, and its anti-inflammation pharmacological activity may be related to the inhibition of M1 macrophage polarization and NF-κB activation through activating AMPK/SIRT1.

Keywords:  AMPK; Atractylodes macrocephala; Gouty arthritis; Hyperuricemia; Macrophage polarization; NF-κB; SIRT1

DOI:  https://doi.org/10.2174/1386207325666220603101540
Foods. 2022 May 30. pii: 1606. [Epub ahead of print]11(11):

Octacosanol Modifies Obesity, Expression Profile and Inflammation Response of Hepatic Tissues in High-Fat Diet Mice.

Jie Bai, Tao Yang, Yaping Zhou, Wei Xu, Shuai Han, Tianyi Guo, Lingfeng Zhu, Dandan Qin, Yi Luo, Zuomin Hu, Xiaoqi Wu, Feijun Luo, Bo Liu, Qinlu Lin.

  The incidence of obesity has increased significantly on account of the alterations of living habits, especially changes in eating habits. In this study, we investigated the effect of octacosanol on lipid lowering and its molecular mechanism. High-fat diet (HFD)-induced obesity mouse model was used in the study. Thirty C57BL/6J mice were divided into control, HFD, and HFD+Oct groups randomly, and every group included ten mice. The mice of HFD+Oct group were intragastrically administrated 100 mg/kg/day of octacosanol. After 10 weeks for treatment, our results indicated that octacosanol supplementation decreased the body, liver, and adipose tissues weight of HFD mice; levels of TC, TG, and LDL-c were reduced in the plasma of HFD mice; and level of HDL-c were increased. H&E staining indicated that octacosanol supplementation reduces the size of fat droplets of hepatic tissues and adipose cells comparing with the HFD group. Gene chip analysis found that octacosanol regulated 72 genes involved in lipid metabolism in the tissues of liver comparing to the HFD group. IPA pathway network analysis indicated that PPAR and AMPK may play a pivotal role in the lipid-lowering function of octacosanol. Real-time quantitative PCR and Western blot showed that the octacosanol supplementation caused change of expression levels of AMPK, PPARs, FASN, ACC, SREBP-1c, and SIRT1, which were closely related to lipid metabolism. Taken together, our results suggest that octacosanol supplementation exerts a lipid-decreasing effect in the HFD-fed mice through modulating the lipid metabolism-related signal pathway.

Keywords:  AMPK; NF-κB; gene chip; hyperlipidemia; lipid metabolism; octacosanol

DOI:  https://doi.org/10.3390/foods11111606
Aquat Toxicol. 2022 May 20. pii: S0166-445X(22)00130-8. [Epub ahead of print]249 106204

Eucalyptol relieves imidacloprid-induced autophagy through the miR-451/Cab39/AMPK axis in Ctenopharyngodon idellus kidney cells†.

Xiaojing Li, Yujie Yao, Jinliang Wang, Zhiqiang Shen, Zhihui Jiang, Shiwen Xu.

  Imidacloprid (IMI) is a widely used neonicotinoid insecticide that has toxic effects on nontarget organisms. 1,8-Cineole (eucalyptol) is purified from essential oils in several aromatic plants and can prevent xenobiotic toxicity. The kidney is a major organ for xenobiotic elimination and thus has high risk of exposure. The purpose of this research was to clarify the effect of IMI exposure on autophagy in fish kidney cells, determine the potential of eucalyptol to provide cytoprotection from the toxicity of the neonicotinoid pesticide IMI, and identify its mechanism of action. Therefore, the Ctenopharyngodon idellus kidney cell line (CIK cell) was treated with 20 mg/L IMI and/or 20 μM eucalyptol for 48 h as the research objective. The results showed that IMI exposure induced autophagy accompanied by advanced autophagy markers BNIP3, Beclin1 and LC3Ⅱ/Ⅰ in CIK cells, reduced the levels of miR-451, increased the expression of Cab39 and AMPK, inhibited AKT/mTOR signaling, and activated the JNK pathway. Eucalyptol treatment alleviated IMI-induced autophagy and relieved the activation of autophagy-associated signals. These results indicate that eucalyptol could alleviate IMI-induced autophagy through the miR-451/Cab39/AMPK axis in fish kidney cells. These results partly explained the mechanism of biological threat on fish under IMI exposure and the potential application value of EUC in aquaculture.

Keywords:  1,8-Cineole; Autophagy; Fish kidney cell; Imidacloprid; miR-451/Cab39/AMPK axis

DOI:  https://doi.org/10.1016/j.aquatox.2022.106204
World J Biol Psychiatry. 2022 Jun 08. 1-33

Metformin attenuates depressive-like behavior of methamphetamine withdrawal in mice: A mechanistic approach.

Mir-Jamal Hosseini, Aisan Arabiyan, Sina Mobassem, Hamed Ghavimi.

  Objectives Methamphetamine (METH) as a potent psychostimulant drug with a high potency of dependence rate that results in neurotoxicity has become a major drug of abuse in many parts of the world. Unfortunately, there is limited evidence regarding treatment of METH withdrawal syndrome. Therefore, we aimed to investigate whether metformin mitigate the methamphetamine (METH) withdrawal syndrome in male mice. Based on the literature, depression and anxiety are the major METH withdrawal symptoms. Methods: Here, METH (2 mg/kg) was administered to mice twice a day for 14 constitutive days to induce animal model of METH-induced withdrawal syndrome. To do this, mice in control group and those with METH withdrawal syndrome were divided into treatment (receiving metformin in 3 doses of 50,100 and 200 mg/kg for 10 days) and non-treatment sub-groups. Following the behavioral test, the animals were sacrificed; their hippocampus was dissected to measure oxidative stress parameters and expression of cellular energy homeostasis and immune-inflammatory genes. Results: Our data revealed that metformin provoked antidepressant effects in behavioral tests through AMPK overexpression as an important mitochondrial energetic sensor and inhibition of Tlr4 overexpression in the immune system gene expression. In addition, metformin was able to improve oxidative stress biomarkers and neuronal damage in the hippocampus and restore cellular energy homeostasis and immune system gene expression. Conclusions: The data suggested that metformin can influence the hippocampus through targeting mitochondria and their performance, and consequently, neuroinflammation responses and brain metabolic changes. It is supposed to be a new therapeutic option in clinical trials of depression and anxiety following METH withdrawal treatment.

Keywords:  AMPK ; Anxiety; Depression; Metformin; Methamphetamine (METH); Mice; Oxidative stress; Tlr4 ; Withdrawal syndrome

DOI:  https://doi.org/10.1080/15622975.2022.2086294
Mol Oncol. 2022 Jun 08.

PGAM1 regulation of ASS1 contributes to the progression of breast cancer through the cAMP/AMPK/CEBPB pathway.

Min Liu, Runmei Li, Min Wang, Ting Liu, Qiuru Zhou, Dong Zhang, Jian Wang, Meng Shen, Xiubao Ren, Qian Sun.

  Phosphoglycerate mutase 1 (PGAM1) is a crucial glycolytic enzyme, and its expression status has been confirmed to be associated with tumor progression and metastasis. However, the precise role and other biological functions of PGAM1 remain unclear. Here, we report that PGAM1 expression is upregulated and related to poor prognosis in patients with BC. Functional experiments showed that knockdown of PGAM1 could suppress the proliferation, invasion, migration and epithelial-mesenchymal transition (EMT) of BC cells. Through RNA sequencing, we found that argininosuccinate synthase 1 (ASS1) expression was markedly upregulated in BC cells following PGAM1 knockdown and it is required to suppress the malignant biological behaviors of BC cells. Importantly, we demonstrated that PGAM1 negatively regulates ASS1 expression through the cAMP/AMPK/CEBPB axis. In vivo experiments further validated that PGAM1 promoted tumor growth in BC by altering ASS1 expression. Finally, immunohistochemical analysis showed that downregulated ASS1 levels were associated with PGAM1 expression and poor prognosis in patients with BC. Our study provides new insight into the regulatory mechanism of PGAM1-mediated BC progression that might shed new light on potential targets and combination therapeutic strategies for BC treatment.

Keywords:  AMPK; ASS1; CEBPB; PGAM1; breast cancer

DOI:  https://doi.org/10.1002/1878-0261.13259
J Exp Clin Cancer Res. 2022 Jun 10. 41(1): 197

Retraction Note: Curcumin synergizes with 5-fluorouracil by impairing AMPK/ULK1-dependent autophagy, AKT activity and enhancing apoptosis in colon cancer cells with tumor growth inhibition in xenograft mice.

Pan Zhang, Ze-Lin Lai, Hui-Fen Chen, Min Zhang, An Wang, Tao Jia, Wen-Qin Sun, Xi-Min Zhu, Xiao-Feng Chen, Zheng Zhao, Jun Zhang.

DOI: https://doi.org/10.1186/s13046-022-02409-y